Alzheimer's disease is a disease attended with a wide range of symptoms of neurodegenerative dementia. Generation of amyloid β peptides (Aβ) is considered to be a cause of Alzheimer's disease (Selkoe, D. J. (2001) Physiol. Rev. 81, 741-766; and Iwata, N. et al., (2001) Science 292, 1550-1552). An amyloid precursor protein (APP) is cleaved with β-secretase, and as a result, a soluble NH2-terminal fragment (APPsβ) and a 12-kDa COOH-terminal fragment (C99) are generated. The latter fragment remains bound to a membrane. C99 is further cleaved with γ-secretase, and then pathogenic Aβ is generated (De Strooper, B. et al., (1998) Nature (London) 391, 387-390; and Wolfe, M. S. et al., (1990) Nature (London) 398, 513-517.) Via another pathway, APP is cleaved with α-secretase in an Aβ sequence, and as a result, a soluble NH2-terminal fragment (APPsα) and a 10-kDa membrane-bound COOH-terminal fragment (C83) are generated (Buxbaum, J. D. et al., (1998) J. Biol. Chem. 273, 27765-27767; and Lammich, S. et al., (1999) Proc. Natl. Acad. Sci. USA 96, 3922-3927).
It has been reported that there are a large number of markers showing a correlation with Alzheimer's disease. The relationship of a majority of such markers with the pathological changes is unknown, and the diagnostic value has not been necessarily established. Markers that are directly associated with such pathological changes include a decrease in one type of amyloid β peptide (Aβ 1-42) consisting of 42 amino acids contained in cerebrospinal fluid. However, since such Aβ peptide is easily aggregated to create a precipitate, it becomes a cause of diseases. Accordingly, the amount of free Aβ is very small, and thus it is theoretically difficult to use such a trace amount of Aβ as a diagnostic marker. As a matter of fact, it has been known that the amount of such Aβ peptide is fluctuated only after the symptoms of Alzheimer's disease become severe. Thus, such Aβ peptide cannot be used as an early diagnostic marker. On the other hand, an increase of the phosphorylated tau protein in cerebrospinal fluid is observed even at an early stage of the disease, and thus it is considered the most excellent biomarker. However, when such phosphorylated tau is increased, neuron death has already progressed. Accordingly, even if a treatment is initiated at such stage, a complete recovery of nerve function cannot be expected. In addition, when such markers are used in measurements using cerebrospinal fluid (lumbar puncture fluid). In order to collect such material, a special technique is necessary. Since it puts a burden upon patients, a method using the aforementioned markers cannot become a mass screening method.
The present inventors have found that β-secretase cleaves not only an amyloid precursor protein, but also α2,6-sialyltransferase. Based on this discovery, the inventors have measured the cleaved free α2,6-sialyltransferase. Thereafter, regarding the fact that such α2,6-sialyltransferase can be used in diagnoses as a marker for an increase in β-secretase activity, the inventors have previously filed a patent application (Japanese Patent Application No. 2003-382374, which has been unpublished at the time of filing of the present application). In the aforementioned patent application, an antibody that specifically recognizes the cleavage site of human soluble α2,6-sialyltransferase is used. Use of this antibody has enabled quantification of soluble α2,6-sialyltransferase in human blood or cerebrospinal fluid. Thus, a method for monitoring β-secretase activity has been provided. However, in general, only a trace amount of glycosyltransferase is contained in body fluid, and thus the detection efficiency is not necessarily high. Further, a cleavage site-recognizing antibody has been required for detection of such glycosyltransferase.